Phenytoin binding

A major problem arises in clinical practice when only total (protein bound + free) phenytoin concentrations are measured and used to guide therapy of patients with severely impaired renal function. The decreases in phenytoin binding that occur in these patients result in commensurate decreases in total plasma levels (Figure 5.2). Even though therapeutic and toxic pharmacologic effects are correlated with unbound rather than total phenytoin concentrations in plasma, the decrease in total concentrations can mislead physicians to increase phenytoin doses inappropriately. Fortunately, rapid ultrafiltration procedures are available that make it possible to measure free phenytoin concentrations in these patients on a routine basis. 

In obese women, the AAG concentrations are doubled, and the unbound plasma fraction of propranolol is 30 /o lower than that in women with normal body weight.f In the obese, the albumin concentrations, and phenytoin binding are normal, whereas diazepam binding is slightly reduced. In undernourished or hospitalized patients, the AAG concentrations are 30 0% higher than those in unhospitalized patients, and the propranolol free fraction is reduced by approximately, 30%. A marked decrease in albumin concentration has been reported in malnutrition, and it seems associated with a reduction in protein synthesis. ... 

Severe poisoning in a hypoalbuminemic neonate responded unusually to peritoneal dialysis, possibly because of reduced phenytoin binding to plasma proteins (SEDA-16, 73). 

Unbound concentration measurements provide the best means for individualizing phenytoin therapy in patients with renal insufficiency. They are however not widely available nor routinely utilized. Therefore methods have been presented to equate an observed total concentration in patients with ESKD receiving hemodialysis treatment to what would be expected in patients with normal renal function. Liponi and associates suggested a method by which the total phenytoin concentration (Cni ° ) in patients with creatinine clearance values of 10 to 24 mL/min or less than 10 mL/min can be equated to the concentration that would be observed if plasma protein concentrations and phenytoin-binding characteristics were normal. A patient s equated total phenytoin concentration (Ce ° ) would thus equal ... 

M2. Mabuchi, H., and Nakahashi, H., A major inhibitor of phenytoin binding to serum protein in uremia. Nephron 48, 310-314 (1988). 

Phenytoin is indicated for initial monotherapy or adjunct treatment of complex partial or tonic-clonic seizures, convulsive status epilepticus, and prophylaxis. It often is selected for initial monotherapy because of its high efficacy and relatively low incidence of side effects (29). Phenytoin is not used in the treatment of absence seizures, because it may increase their frequency of occurrence (30,31). Phenytoin binds to and stabilizes the inactivated state of sodium channels, thus producing a use-dependent blockade of repetitive firing and inhibition of the spread of seizure activity to adjacent cortical areas. 

J. Chen, C. Phnmacht and D. S. Hage, Studies of phenytoin binding to human serum albumin by high-performance affinity chromatography, /. Chromatogr., A, 2004, 809,137-145. 

Source From Studies of phenytoin binding to human serum albumin by high-performance affinity chromatography, in J. Chromatogr. 

Class IB drugs like lidocaine, phenytoin or mex-iletine preferentially bind to the inactivated state. Lidocaine, a local anaesthetic, can be used intravenously for antiarrhythmic treatment. It is one of the classical dtugs used in emergency medicine for the... 

Some AEDs, especially phenytoin and valproate, are highly bound to plasma proteins. When interpreting a reported concentration for these drugs, it is important to remember that the value represents the total (i.e., bound and unbound) concentration in the blood. Because of differences in the metabolism of these drugs, the clinical effects of altered protein binding are different for different drugs. 

Normally, 88% to 92% of phenytoin is bound to plasma protein, leaving 8% to 12% unbound. The unbound component is able to leave the blood to produce the clinical effect in the CNS, produce dose-related side effects in the CNS and at other sites, distribute to other peripheral sites, and be metabolized. Certain patient groups are known to have decreased protein binding, resulting in an increased percentage of drug that is unbound. These patient groups include ... 

Due to the Michaelis-Menten metabolism of phenytoin, alterations in its protein binding will result in increased severity of dose-related adverse effects. In patients with suspected changes in protein binding, it is useful to measure unbound phenytoin concentrations. 

When valproate protein binding is altered, the risk for severe dose-related adverse effects is much less compared to phenytoin. Michaelis-Menten metabolism is not a factor with valproate, so hepatic enzymes are able to efficiently metabolize the additional unbound portion. 

Mays, D.C. et al. 1995. Metabolism of phenytoin and covalent binding of reactive intermediates in activated human neutrophils. Biochem. Pharmacol. 50 367-80. 

Roy, D. and Snodgrass W.R. 1990. Covalent binding of phenytoin to protein and modulation of phenytoin metabolism by thiols in A/J mouse liver microsomes. J. Pharmacol. Exp. Ther. 252 895. 

Highly protein-bound drugs In vivo, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. However, use caution when raloxifene is coadministered with other highly protein-bound drugs, such as diazepam, diazoxide, and lidocaine. 

Absorption/Distrlbutlon - Phenytoin is slowly absorbed from the small intestine. Rate and extent of absorption varies and is dependent on the product formulation. Bioavailability may differ among products of different manufacturers. Administration IM results in precipitation of phenytoin at the injection site, resulting in slow and erratic absorption, which may continue for up to 5 days or more. Plasma protein binding is 87% to 93% and is lower in uremic patients and neonates. Volume of distribution averages 0.6 L/kg. Phenytoin s therapeutic plasma concentration is 10 to 20 mcg/mL, although many patients achieve complete seizure control at lower serum concentrations. 

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